Despite preventive measures that have been developed, dental caries persists as a major worldwide disease. Although not the most devastating, this infectious disease may be the most prevalent and costly disease in developing, as well as industrialized countries. Secretory IgA is a first line of defense against pathogens that invade through the oral cavity, including Streptococcus mutans (the bacterium associated with caries initiation). Despite extensive efforts on the development of a mucosal vaccine against microbial pathogens, (e.g., S. mutans), this route of immunization is only recently being recognized as the preferred route, compared to the conventional systemic route in inducing protective immunity. Recent preliminary human immunization studies have consistently found salivary S-IgA responses to S. mutans when liposomal antigens are given orally; however, the salivary responses were of low magnitude and short duration. In order to improve the magnitude and persistence of salivary responses to the mucosal liposomal vaccine, two new routes of immunization and adjuvants will be investigated in this proposal. Specifically, the proposed studies will determine the effectiveness of three liposome vaccines containing S. mutans glucosyltransferase (Cholera toxin B subunit [CTB]-Liposomes, monophosphoryl lipid A [MPL]-Liposomes, Conventional Liposomes) to induce oral mucosal responses when administered by gastric, nasal, or topical routes in an experimental rat caries model. The results of the proposed animal studies, and those of previous clinical studies, are intended to provide supporting evidence and rationale for the design of human protocols aimed at inducing potential salivary immune responses to S. mutans vaccines by FDA Phase I studies. Following a dose response study, a double blind FDA Phase II clinical study (involving experimental and control groups of 100 subjects) is proposed to study the immunogenicity and efficacy of the identified optimal liposomal S. mutans vaccine and route. The objective of this proposal is to identify a "candidate" vaccine against S. mutans-induced dental caries. It is suggested that these studies will enhance the design and development of a dental caries vaccine, as well as liposomal-immunization strategies for use in inducing protective mucosal responses to various other pathogen-induced diseases. It is anticipated by the applicants that, pending favorable identification of an immunization route and delivery system, a candidate mucosal vaccine against dental caries will be ready for field trials (FDA Phase III studies) upon completion of these studies.